Implantable drug-delivery devices, and apparatus and methods for refilling the devices

ABSTRACT

In various embodiments, a needle is employed in refilling drug-delivery devices.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to and the benefit of, and incorporatesherein by reference in its entirety, U.S. Provisional Patent ApplicationNo. 61/018,747, which was filed on Jan. 3, 2008.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The U.S. Government has a paid-up license in this invention and theright in limited circumstances to require the patent owner to licenseothers on reasonable terms as provided for by the terms of Grant Nos.ERC EEC-0310723 and EEC-0547544 awarded by the National ScienceFoundation.

TECHNICAL FIELD

In various embodiments, the invention relates to implantabledrug-delivery devices and to apparatus and methods for refilling suchdevices.

BACKGROUND

Medical treatment often requires the administration of a therapeuticagent (e.g., medicament, drugs, etc.) to a particular part of apatient's body. Some maladies, however, are difficult to treat withcurrently available therapies and/or require administration of drugs toanatomical regions to which access is difficult to achieve.

A patient's eye is a prime example of a difficult-to-reach anatomicalregion, and many vision-threatening diseases, including retinitispigmentosa, age-related macular degeneration (AMD), diabeticretinopathy, and glaucoma, are difficult to treat with many of thecurrently available therapies. For example, oral medications can havesystemic side effects; topical applications may sting and engender poorpatient compliance; injections generally require a medical visit, can bepainful, and risk infection; and sustained-release implants musttypically be removed after their supply is exhausted.

Another example is cancer, such as breast cancer or meningiomas, wherelarge doses of highly toxic chemotherapies, such as rapamycin,bevacizumab (e.g., Avastin®), or irinotecan (CPT-11), are typicallyadministered to the patient intravenously, which may result in numerousundesired side effects outside the targeted area.

Implantable drug-delivery devices, which may have a refillable drugreservoir, cannula, and check valve, etc., generally allow forcontrolled delivery of pharmaceutical solutions to a specified target.As drug within the drug reservoir depletes, the physician can refill thereservoir with, for example, a syringe, while leaving the deviceimplanted within the patient's body.

If, however, the syringe needle is inadvertently inserted too far intothe device during the refilling, the device can be damaged. Such damagemay necessitate removal of the device and its replacement with another,thereby obviating some of the advantage of using the device. Even if thedevice is not damaged, insertion of the needle too far into the devicecan, for example, embed the needle tip in the bottom wall of thedevice's reservoir, thereby clogging the needle's lumen. Additionally,the improper insertion of the needle into the device may lead to thedelivery of the drug into an improper location.

A need exists, therefore, for improved implantable drug-deliverydevices, and apparatus and methods for refilling such devices.

SUMMARY OF THE INVENTION

In various embodiments, the present invention features apparatus andmethods for refilling, in situ, a drug-delivery device implanted withina patient's body. The apparatus generally contain features, and themethods typically contain steps, that allow the refilling to occur in amanner that minimizes the risk of damage to the device, and therebymaximizes its effective lifetime. For example, embodiments of arefilling needle described herein employ a needle depth gauge to limitthe degree to which the needle penetrates the drug-delivery deviceduring a refilling procedure. As another example, the drug-deliverydevice itself may include a stop to limit the extent of the needle'spenetration therein. Moreover, to aid a physician in locating a needleentry port of the drug-delivery device, and to protect the patient frominadvertent punctures by the needle, embodiments of the invention employa visualization ring that identifies the needle entry port. Thesefeatures, together with others, facilitate the rapid refilling of thedrug-delivery device, while minimizing the risk of damage to the deviceand injury to the patient. Thus, the time spent by a physician inrefilling the drug-delivery device is reduced (which may generate a costsavings), the useful life of the drug-delivery device may be lengthened,and the need to replace drug-delivery devices damaged during the courseof attempts to refill them is reduced.

In general, in one aspect, embodiments of the invention feature a needlefor refilling an implantable drug-delivery device. The drug-deliverydevice may have a needle entry port that includes a throat for receivingthe needle therethrough. For its part, the needle may include a hollowshaft that terminates in a tip, a fluid exit port along the shaftproximate to the tip, and means for limiting the extent of entry of theneedle into the entry port. In one embodiment, the needle tip isconically-shaped. The fluid exit port of the needle may be positionedintermediate to the tip and the limitation means.

In various embodiments, the limitation means includes a stop on theneedle shaft. For example, the stop may be a ring surrounding andfixedly mounted to the shaft. The ring may have an outer diameterexceeding a width of the entry port's throat. Alternatively, the stopmay be spherically-shaped, cylindrically-shaped, rectangularly-shaped,or pyramidally-shaped. In certain embodiments, the limitation means isconstructed of a metal, a plastic, and/or a composite material. Thelimitation means may be, for example, constructed of a biocompatiblematerial, such as polydimethylsiloxane (PDMS). (Although the ensuingdiscussion refers primarily to PDMS, this is for convenience, andreferences to PDMS are intended to connote any suitably biocompatibleform of polydiorganosiloxane (i.e., silicone) polymer.) Other exemplarymaterials from which the limitation means may be constructed includepolyimide, polypropylene, polyetheretherketone (PEEK), polycarbonate, anacetyl film, polyoxymethylene plastic, gold, stainless steel, nickel,chrome, and combinations thereof.

In general, in another aspect, embodiments of the invention feature animplantable drug-delivery device. The drug-delivery device includes adrug reservoir, a needle entry port, and a vestibule. The needle entryport may include a throat for receiving a refill needle therethrough.The throat may open into the vestibule, which may (i) be wider than thethroat, (ii) include a stop on a wall opposite the throat for haltingprogress of a needle into the vestibule through the throat, and (iii) bein fluid communication with the drug reservoir.

In various embodiments, the drug-delivery device also includes a checkvalve that is located between the vestibule and the drug reservoir. Forits part, the needle entry port may also include a self-sealing material(e.g., at its top surface). In one embodiment, the stop within thevestibule is sized so as to halt the progress of a needle that includesan exit port at a point at which the exit port is in fluid communicationwith the vestibule. A top surface of the stop may be cup-shaped. Incertain embodiments, the stop is constructed of a metal, a plastic,and/or a composite material. The stop may be, for example, constructedof a biocompatible material, such as PDMS. Other exemplary materialsfrom which the stop may be constructed include polyimide, polypropylene,PEEK, polycarbonate, an acetyl film, polyoxymethylene plastic, gold,stainless steel, nickel, chrome, and combinations thereof.

In general, in yet another aspect, embodiments of the invention featurean implantable drug-delivery device that includes a drug reservoir, aneedle entry port, and a visualization ring surrounding the needle entryport. The needle entry port may include a throat for receiving a refillneedle therethrough. The throat may open into a vestibule that is influid communication with the drug reservoir. For its part, thevisualization ring may be visible through ocular tissue (e.g., apatient's conjunctiva) so as to visually indicate the position of theneedle entry port.

In various embodiments, the visualization ring is constructed of amaterial that is biocompatible and/or withstands penetration by therefill needle. The visualization ring may include one or morefluorescent pigments, such as a luminescent aerogel, a nanoparticle, aphthalocyanine (PC) pigment, fluorescein isothiocyanate, rhodamine,coumarin, cyanine, an Alexa Fluor, a DyLight Fluor, a quantum dot, agreen fluorescent protein, and/or a luciferin. In another embodiment,the visualization ring includes a light emitting diode. Alternatively, alight emitting diode present in the drug-delivery device may be locatedaway from the visualization ring and optical fiber may be used toconduct light from the light emitting diode to and around thevisualization ring. The visualization ring may also include a materialthat enhances surface echogenicity and acoustic shadowing. Electronicsmay also be present in the drug-delivery device in order to move orvibrate the visualization ring. In yet another embodiment, thevisualization ring includes a magnetic material.

In general, in still another aspect, embodiments of the inventionfeature a method for refilling a drug-delivery device implanted within apatient. The method includes inserting, into a needle entry port of thedrug-delivery device, a distal tip of a needle that includes a hollowshaft and a stop on the shaft. The needle may then be advanced into theneedle entry port until the stop limits further entry of the needle intothe entry port. Drug may be delivered through the hollow shaft of theneedle, out a fluid exit port positioned along the shaft of the needleproximate the tip, and into the drug-delivery device. In accordance withthis method, the stop may be a ring that surrounds the shaft of theneedle and that has an outer diameter exceeding a width of the entryport.

In general, in a further aspect, embodiments of the invention featureanother method for refilling a drug-delivery device implanted within apatient. The method includes inserting, into a needle entry port of thedrug-delivery device, a distal tip of a needle. The needle may then beadvanced through the needle entry port into a vestibule of thedrug-delivery device until a stop positioned on a wall of the vestibuleopposite the needle entry port halts further entry of the needle. Drugmay be delivered through a hollow shaft of the needle, out a fluid exitport positioned along the shaft of the needle proximate the tip, andinto the vestibule. The stop may halt further entry of the needle at apoint at which the exit port of the needle is in fluid communicationwith the vestibule.

In various embodiments, these methods include locating, prior toinserting the distal tip of the needle into the needle entry port, avisualization ring that visually indicates the position of the needleentry port. The visualization ring may surround the needle entry portand be visible through the patient's conjunctiva.

These and other objects, along with advantages and features of theembodiments of the present invention herein disclosed, will become moreapparent through reference to the following description, theaccompanying drawings, and the claims. Furthermore, it is to beunderstood that the features of the various embodiments described hereinare not mutually exclusive and can exist in various combinations andpermutations.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally refer to the sameparts throughout the different views. Also, the drawings are notnecessarily to scale, emphasis instead generally being placed uponillustrating the principles of the invention. In the followingdescription, various embodiments of the present invention are describedwith reference to the following drawings, in which:

FIG. 1 illustrates a plan view of an implantable drug-delivery device inaccordance with one embodiment of the invention;

FIG. 2 schematically illustrates the internal structure between a needleentry port and a drug reservoir in accordance with one embodiment of theinvention;

FIG. 3 is an elevation view of a refill needle in accordance with oneembodiment of the invention;

FIG. 4 schematically illustrates a refill needle, having a stop fixedlymounted thereto, inserted within a portion of a drug-delivery device inaccordance with one embodiment of the invention;

FIG. 5 schematically illustrates a refill needle inserted within aportion of a drug-delivery device, having a stop fixedly mounted to onewall of a vestibule, in accordance with one embodiment of the invention;and

FIG. 6 is a sectional view of a patient's eye illustrating implantationtherein of a drug-delivery device in accordance with one embodiment ofthe invention.

DESCRIPTION

In general, embodiments of the present invention pertain todrug-delivery devices implantable within a patient's body, such as, forexample, within the patient's eye, and to apparatus and methods forrefilling those devices. In certain embodiments, an implantabledrug-delivery device combines small size and a refillable reservoir. Thesmall size minimizes discomfort from the device to the patient, whilethe refillable reservoir allows the device to be refilled in situ,rather than being replaced. As such, a fluid, such as a solution of adrug, can be supplied to the patient over extended periods of time.

FIG. 1 schematically illustrates an exemplary implantable drug-deliverydevice 100. The exemplary device 100 includes a base 104, a refillabledrug reservoir 108, a drug-delivery cannula 112 in fluid communicationwith the refillable drug-reservoir 108, and a needle entry port 116 influid communication with the refillable drug reservoir 108 as furtherdescribed below. In general, the refillable drug reservoir 108 holds thetherapeutic fluid to be delivered, while the cannula 112 directs thefluid to the targeted site. The cannula 112 may be tapered to facilitateits insertion into, for example, a patient's eye. In general, the drugreservoir 108 can be refilled by inserting a refill needle 120 into andthrough the needle entry port 116. As described, for example, in U.S.Patent Application Publication No. 2008/0039792 entitled “MEMS Deviceand Method for Delivery of Therapeutic Agents,” the disclosure of whichis hereby incorporated herein by reference in its entirety, thedrug-delivery device 100 may be mechanically (e.g., manually) orelectrolytically actuated to deliver the therapeutic fluid to a targetedsite.

FIG. 2 schematically illustrates the internal structure of thedrug-delivery device 100 between the needle entry port 116 and the drugreservoir 108 in accordance with one embodiment of the invention. Asillustrated, the needle entry port 116 includes a surface 124 and athroat 128 for receiving the refill needle 120 therethrough. The throat128 opens into a vestibule 132 that is in fluid communication (through,for example, a check valve 136) with the drug reservoir 108. The refillneedle 120 pierces, as depicted, the surface 124 of the needle entryport 116, travels through its throat 128, and thereby gains access tothe vestibule 132. In one embodiment, injection of a therapeutic fluidfrom the needle 120 into the vestibule 132 forces the fluid through thecheck valve 136 and into the reservoir 108, thereby refilling thereservoir 108.

As also illustrated in FIGS. 1 and 2, a visualization ring 140 maysurround the needle entry port 116 of the implantable drug-deliverydevice 100. In one embodiment, the visualization ring 140 is made of amaterial or pigment that is visible through ocular tissue (e.g., througha patient's conjunctiva) so as to visually indicate a position of theneedle entry port 116 to a user of the device 100 (e.g., a physician)when the device 100 is implanted within a patient's eye. In addition,the material or pigment forming the visualization ring 140 may bebiocompatible and/or able to withstand penetration by the refill needle120 if and when the refill needle 120 is accidently placed in contacttherewith. Exemplary materials from which the visualization ring 140 maybe constructed include, but are not limited to, PDMS, polyimide, PEEK,gold, stainless steel, and titanium. The material or pigment forming thevisualization ring 140 may optionally fluoresce when exposed to aparticular type of light, such as ultraviolet (UV) light. In daylight,fluorescent pigments have a white or light color and are thereforegenerally cosmetically invisible. Under excitation by UV radiation,however, the fluorescent pigments typically irradiate an intensivefluorescent color. Exemplary pigments that may form the visualizationring 140, or a portion thereof, include, but are not limited to,luminescent aerogels, nanoparticles (e.g., silicon nanoparticles),phthalocyanine (PC) pigments, fluorescein isothiocyanate, rhodamine(TRITC), coumarin, cyanine, Alexa Fluors, DyLight Fluors, quantum dots,green fluorescent proteins, and/or luciferins. By using such pigments,the visualization ring 140 and its substrates may generally becosmetically invisible until such time as the physician exposes the ring140 to UV light. At that point, the physician can easily visualize thering 140, either visually or with the aid of, for example, afluorescence stereo microscope.

The visualization ring 140 may also be made with materials that enhancesurface echogenicity and acoustic shadowing so that the physician maybetter visualize the needle entry port 116 when using certain imagingdevices. Such materials include metals, semiconductors, and advancedcomposite materials that cause the visualization ring 140 to become morereflective or absorbent to ultrasound waves or infrared light (incontrast to the other materials on the non-ring portions of thedrug-delivery device 100 that are not desired to be visualized) duringsuch times as when the physician uses an ultrasound scanner, an opticalcoherence tomography (OCT) visualization tool, or other coherencescanner for visualizing the ring 140 subcutaneously. For example, if theouter shell of the drug-delivery device 100 is made of polyimide (a lessreflective material), but the visualization ring 140 is lined with gold(a more reflective material), then the visualization ring 140 will bemore easily visualized by the physician when using an OCT scanner orultrasound scanner since the light, laser, or sound will be reflecteddifferently by the gold.

In another embodiment, the visualization ring 140 includes one or morelight emitting diodes (LEDs) that illuminate during the desired time ofrefilling. For example, the drug-delivery device 100 may include aninternal power supply (e.g., a battery) and other electronics to supplypower to the LEDs. Then, the physician may activate the power supply andelectronics wirelessly (e.g., using a device that emits aradio-frequency (RF) signal) to turn the LEDs on just prior to refillingthe drug-delivery device 100. Alternatively, where it is desired tohermetically package the electronic devices (including the LEDs) withinthe drug-delivery device 100, the LEDs may be located in a differentpart of the drug-delivery device 100 (e.g., distant from thevisualization ring 140) and a conduit, such as a bundle of opticalfiber, may be used to conduct the light from the LEDs to thevisualization ring 140 and also around the visualization ring 140.

In yet another embodiment, the visualization ring 140 and/or the needleentry port 116 moves up and down, or vibrates, in a manner that givesthe physician a tactile sensation confirming the location of thevisualization ring 140 and/or needle entry port 116. Again, suchmovement and/or vibration may be imparted to the visualization ring 140and/or the needle entry port 116 through the use of electronics internalto the drug-delivery device 100. Those electronics may be activatedremotely through, for example, a handheld device emitting an RF signal.

In still another embodiment, the visualization ring 140 includes amagnetic material. For example, the visualization ring 140 may be made,at least in part, from a ferromagnetic material alone, or it may includea ferromagnetic material encased in a ceramic. The refill needle 120used in combination with such a visualization ring 140 may likewisecontain magnetic materials, for example on a tip 208 and/or shaft 212thereof, and/or on a stop 224 connected thereto (see FIG. 3). In thisway, the magnetic materials of the visualization ring 140 may attractthe magnetic materials of the refill needle 120, thereby aiding thephysician in locating the needle entry port 116. In addition, themagnetic materials of the visualization ring 140 and the refill needle120 may aid in aligning the shaft 212 of the refill needle 120 with theelongate axes of the throat 128 and vestibule 132, thereby preventingthe needle 120 from contacting (and potentially puncturing) a sidewall144 of the vestibule 132.

Since the needle entry port 116 may be very small, and the physician maybe injecting drugs in an invasive manner, it is often useful to add asecondary or tertiary confirmatory signal for the location of thevisualization ring 140 and the needle entry port 116, such as sight,sound, tactile sensation, and/or magnetic interaction.

In one embodiment, as illustrated in FIG. 2, the visualization ring 140is embedded into (and thus completely surrounded by) the materialforming the surface 124 of the needle entry port 116. In this way, thevisualization ring 140 does not come into contact with the patient'sbody or with any medications delivered to the device 100 by the refillneedle 120. In certain embodiments, this is important. For example, theuse of some materials in the visualization ring 140, such as rhodaminepigments, can be toxic to the patient's body or degrade over time if notproperly sealed with the material forming the surface 124.

The visualization ring 140 may be an annulus and, as illustrated in FIG.2, its inner diameter may define the width w1 of the throat 128 throughwhich the refill needle 120 passes when it is inserted into the needleentry port 116. Moreover, in one embodiment, the width w2 of thevestibule 132 is greater than the width w1 of the throat 128. In thisway, the smaller width w1 of the throat 128 constrains the movement ofthe refill needle 120 as it is advanced into the vestibule 132 and aidsin preventing the needle 120 from contacting (and potentiallypuncturing) the sidewall 144 of the vestibule 132.

In addition to the visualization ring 140, an insertion guider (notshown) may be positioned at a top surface of, or within, the needleentry port 116 to aid in guiding the refill needle 120 along theelongate axis of the vestibule 132 (and not into the sidewall 144). Theinsertion guider may be cylindrical in shape, or have another shape. Inaddition, the insertion guider may be removable and may be placed on topof the needle entry port 116 and mechanically or magnetically locked tothe needle entry port 116 just prior to the refilling procedure.

As mentioned, a physician may pierce the surface 124 of the needle entryport 116 with the refill needle 120 as he or she advances the needle 120into the vestibule 132 of the drug-delivery device 100. In oneembodiment, the material of the surface 124 is self-sealing. Morespecifically, the surface 124 may be formed from a soft plastic materialthat can be punctured with the needle 120 and that reseals itself uponremoval of the needle 120. In one embodiment, the self-sealing materialis able to withstand multiple punctures by the needle 120, and isbiocompatible. Examples of materials that may be employed for theself-sealing material include, but are not limited to, PDMS, parylene C,parylene HT, polycarbonates, polyolefins, polyurethanes, copolymers ofacrylonitrile, copolymers of polyvinyl chloride, polyamides,polysulphones, polystyrenes, polyvinyl fluorides, polyvinyl alcohols,polyvinyl esters, polyvinyl butyrate, polyvinyl acetate, polyvinylidenechlorides, polyvinylidene fluorides, polyimides, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polyethers,polytetrafluoroethylene, polychloroethers, polymethylmethacrylate,polybutylmethacrylate, polyvinyl acetate, nylons, cellulose, gelatin,silicone rubbers and porous rubbers. Where the self-sealing materialincludes a plastic that is capable of leaching or absorbing drugs thatcome into contact with it (e.g., silicone), parylene may be coated overthe plastic so that less drug is exposed to the plastic.

FIG. 3 depicts one embodiment of the refill needle 120. As illustrated,the refill needle 120 includes a proximal end 200 (i.e., an end closestto an operator of the refill needle 120) and an opposite, distal end204. In one embodiment, the distal end 204 of the needle 120 terminatesin a tip 208, such as a conically-shaped tip. The tip 208 may, ofcourse, have another shape suitable for piercing the surface 124 of theneedle entry port 116. For example, as illustrated in FIG. 2, the distalend 204 of the refill needle 120 may be cut (or otherwise formed) at anoblique angle to form an oblique tip 208.

A hollow shaft 212 (i.e., a shaft having a lumen that extendstherethrough) extends from the proximal end 200 of the refill needle 120to a proximal end 216 of the tip 208. In addition, as illustrated, therefill needle 120 may include at least one fluid exit port 220positioned along the shaft 212 (e.g., near the tip 208). For example,the refill needle 120 may include, near the proximal end 216 of the tip208, two fluid exit ports 220 positioned approximately 180° apart aroundthe circumference of the shaft 212. Alternatively, the fluid exitport(s) 220 may be positioned elsewhere along the shaft 212. The fluidexit port(s) 220 is/are in fluid communication with the lumen of thehollow shaft 212. In this way, when the refill needle 120 is positionedwithin the vestibule 132 of the device 100, as further described below,therapeutic fluid may be passed through the hollow shaft 212 of theneedle 120, out its fluid exit port(s) 220, and into the vestibule 132.In addition, the fluid exit port(s) 220 are generally orientedtransverse to the long axis of the refill needle 120. In this fashion,the refill needle 120 may be inserted into the needle entry port 116 ofthe device 100 with reduced risk of occluding the exit port(s) 220 withmaterial cored from the walls of the throat 128.

With reference still to FIG. 3, the refill needle 120 may also include ameans for limiting an extent of entry of the needle 120 into the needleentry port 116. For example, the limitation means may be a stop 224fixedly mounted to the needle shaft 212. As illustrated, the stop 224may be mounted to the shaft 212 at a point proximal to the fluid exitport(s) 220, such that the fluid exit port(s) 220 is/are positionedintermediate to the needle tip 208 and the stop 224. As illustrated inFIG. 4, by positioning the stop 224 an appropriate distance away fromboth the fluid exit port(s) 220 and the distal end 204 of the refillneedle 120, the fluid exit port(s) 220 will be correctly positionedwithin the vestibule 132 of the device 100 when the stop 224 abuts thesurface 124 of the needle entry port 116, and the tip 208 at the distalend 204 of the needle 120 will not contact (or pierce) the bottom wall148 of the vestibule 132. In one embodiment, to achieve this desiredeffect, the stop 224 is positioned at a distance from the fluid exitport(s) 120 that is greater than the height h1 of the throat 128 of theneedle entry port 116, and also at a distance from the distal end 204 ofthe refill needle 120 that is less than the combined height h2 of thethroat 128 and vestibule 132. In this way, the stop 224 decreases thelikelihood of the refill needle 220 penetrating the entire drug-deliverydevice 100 and entering, for example, the patient's eye. The stop 224also prevents the tip 208 of the refill needle 120 from becomingembedded in the bottom wall 148 of the vestibule 132, where the fluidexit port(s) 220 and lumen of the needle 120 may be occluded, therebypreventing therapeutic fluid from being dispensed into the vestibule132.

In one embodiment, as illustrated in FIG. 3, the stop 224 is a ring thatsurrounds the shaft 212 of the refill needle 120. So that the stop 224halts the progress of the refill needle 120 into the vestibule 132 ofthe device 100 (i.e., limits the depth to which the refill needle 120can be inserted into the vestibule 132), the ring, in one embodiment,has an outer diameter d1 that exceeds the width w1 of the throat 128. Inthis way, the stop 224 and the portion of the refill needle 120proximate to the stop 224 are prevented from entering the needle entryport 116. The outer contour of the stop 224 need not take the form of aring. For example, the stop 224 may have an outer shape that isgenerally spherical, cylindrical, rectangular, or pyramidal, or may beshaped in another manner suitable for carrying out the functions of thestop 224 described herein.

The stop 224 may be constructed of a metal, a plastic, a compositematerial, or a combination thereof. The metal, plastic, and/or compositematerial may be biocompatible, or not. In one embodiment, the stop 224is constructed of PDMS. Alternatively, the stop 224 may be constructedof other material, or combinations of materials, that have the requisitemechanical strength to perform the function of the stop 224 describedherein. For example, the stop 224 may also be constructed of polyimide,polypropylene, PEEK, polycarbonate, acetyl film (e.g., acetylcopolymer), polyoxymethylene plastic (e.g., Delrin®), gold, stainlesssteel, nickel, and/or chrome. The stop 224 may also take the form of anintegral, disk-like protrusion from (and extending around) the needleshaft 212, introduced during the manufacture thereof.

In practice, an exemplary refill needle 120 may be prepared by pinchingclosed a hollow 30-gauge needle and deburring the closure to leave aconical tip 208 of approximately 254 μm in height. Two exit ports 220,each measuring approximately 101 μm in diameter, may then drilledthrough refill needle 120 approximately 127 μm above the proximal end216 of the conical tip 208. A stop 224 may then be fabricated bylaser-cutting a thin PDMS membrane into an appropriately sized ringshape. As will be understood by one of ordinary skill in the art, theinner diameter of the ring-shaped stop 224 is determined by the size ofthe outer diameter of the refill needle 120 (i.e., approximately 305 μmfor a 30-gauge needle). The PDMS ring-shaped stop 224 may then be fittedonto the shaft 212 of the needle 120 and secured by, for example, aglue. The location on the shaft 212 to which the ring-shaped stop 224 issecured is chosen as described above.

In another embodiment, rather than fixedly mounting a stop 224 on theoutside of the shaft 212 of the refill needle 120, or in additionthereto, a stop may be positioned within the vestibule 132 of thedrug-delivery device 100 itself. For example, as illustrated in FIG. 5,a stop 152 may be secured to, and caused to extend from, the bottom wall148 of the vestibule 132 (i.e., a wall of the vestibule 132 opposite thethroat 128), for example by gluing the stop 152 to the wall 148. In thisway, the progress of the refill needle 120 into the vestibule 132through the throat 128 halts when the tip 208 of the needle 120 contactsthe stop 152. Again, in this embodiment, the stop 152 may be sized(i.e., in height), and the fluid exit port(s) 220 placed on the shaft212 of the refill needle 120, so that the progress of the needle 120into the vestibule 132 is halted at a point at which the exit port(s)220 is/are in fluid communication with the vestibule 132.

The stop 152 may be a rectangular prism, a cylinder, or any other shapesuitable for carrying out the functions of the stop 152 describedherein. As illustrated in FIG. 5, a top surface 160 of the stop 152 maybe flat. Alternatively, the stop 152 may be shaped as a cup (e.g., thetop surface 160 of the stop 152 may be cup-shaped or concave). In thisway, the stop 152 may also aid in preventing the refill needle 120 fromcontacting, and possibly penetrating, the sidewall 144 of the vestibule132.

In addition, like the stop 224 of the refill needle 120, the stop 152may be constructed of a metal, a hard (e.g., fully cross-linked orreinforced) plastic, a composite material, or a combination thereof. Forexample, the stop 152 may be constructed from a thick layer of PDMS(i.e., a thicker layer than that used for the puncturable surface 124 ofthe needle entry port 116), polyimide, polypropylene, PEEK,polycarbonate, acetyl film (e.g., acetyl copolymer), polyoxymethyleneplastic (e.g., Delrin®), gold, stainless steel, nickel, and/or chrome.The stop 152 may be biocompatible, or not. In general, the stop 152 maybe constructed of any relatively rigid and mechanically robust material,or combinations of materials, that have the requisite mechanicalstrength for performing the functions of the stop 152 described herein.

FIG. 6 schematically illustrates the exemplary drug-delivery device 100implanted in the eye of a patient in accordance with one embodiment ofthe invention. As illustrated, the device 100 is placed upon theconjunctiva of the eye, and the cannula 112 is inserted therethrough into the posterior chamber of the eye. The drug-delivery device 100administers therapeutic fluid to the posterior chamber of the eyethrough the cannula 112 and a check valve 156, which may control thedelivery of the fluid and prevent backflow. In other embodiments, thedevice 100 is used to administer fluid to the anterior chamber of theeye, which is separated from the posterior chamber by the lens.

An operator of the drug-delivery device 100 (e.g., a physician) mayrefill the device 100 in situ (i.e., without having to remove the device100 from the patient's eye). To do so, in one embodiment, the operatorfirst locates the visualization ring 140 of the device 100. The operatormay locate the visualization ring 140 by simple visual inspectionbecause, as described above, the visualization ring 140 is constructedof a material that is visible through the patient's conjunctiva.Moreover, because the visualization ring 140 surrounds the needle entryport 116, it visually indicates the position of that needle entry port116 to the operator.

Once the visualization ring 140 and needle entry port 116 are located,the operator inserts the distal tip 208 of the refill needle 120 intothe needle entry port 116 of the drug-delivery device 100. Morespecifically, the operator may contact the surface 124 of the needleentry port 116 with the distal tip 208 of the refill needle 120, piercethe surface 124 by advancing the needle 120, and further advance theneedle 120 into the throat 128 and then the vestibule 132 of thedrug-delivery device 100. In an embodiment where the refill needle 120includes the stop 224 fixedly mounted to (or integral with) its shaft212, the operator may continue to advance the needle 120 into the needleentry port 116 until the stop 224 contacts the surface 124 of the needleentry port 116, thereby limiting further entry of the needle 120 intothe needle entry port 116. Alternatively, in an embodiment where thevestibule 132 includes the stop 152 fixedly mounted to its bottom wall148, the operator may continue to advance the refill needle 120 into theneedle entry port 116 until the distal tip 208 of the needle 120contacts the stop 152, which then halts further entry of the needle 120into the vestibule 132.

At the point of the stop 224 and/or the stop 152 acting to limit furtherentry of the needle 120 into the vestibule 132, the operator will beassured, as described above, that the exit port(s) 220 of the refillneedle 120 is/are properly placed within the vestibule 132 and in fluidcommunication therewith. The operator may then cause a therapeutic fluid(e.g., a drug in liquid form) to be delivered through the hollow shaft212 of the refill needle 120, out the fluid exit port(s) 220, and intothe vestibule 132 of the drug-delivery device 100. Injection of thetherapeutic fluid from the needle 120 into the vestibule 132 forces thefluid through the check valve 136 and into the reservoir 108, therebyrefilling the reservoir 108.

Accordingly, as described herein, the operator may rapidly refill thedrug-delivery device 100 in situ, while the risk of damage to the device100 and injury to the patient are also minimized.

Having described certain embodiments of the invention, it will beapparent to those of ordinary skill in the art that other embodimentsincorporating the concepts disclosed herein may be used withoutdeparting from the spirit and scope of the invention. For example, thedrug-delivery device 100 may also be implanted in other portions of apatient's body, such as in the sub-arachnoid space of the brain toprovide chemotherapy or to provide another type of treatment for thebrain, near a tumor in any portion of the patient's body to providechemotherapy, or in a pancreas that does not respond well to glucose toprovide agents (e.g., proteins, viral vectors, etc.) that will triggerinsulin release. Accordingly, the described embodiments are to beconsidered in all respects as only illustrative and not restrictive.

1. A needle for refilling an implantable drug-delivery device having aneedle entry port that comprises a throat for receiving the needletherethrough, the needle comprising: a hollow shaft terminating in atip; a fluid exit port along the shaft proximate to the tip; and meansfor limiting an extent of entry of the needle into the entry port. 2.The needle of claim 1, wherein the limitation means comprises a stop onthe shaft.
 3. The needle of claim 2, wherein the stop is a ringsurrounding and fixedly mounted to the shaft, the ring having an outerdiameter exceeding a width of the throat.
 4. The needle of claim 2,wherein the stop is spherically-shaped, cylindrically-shaped,rectangularly-shaped, or pyramidally-shaped.
 5. The needle of claim 1,wherein the limitation means is constructed of a biocompatible material.6. The needle of claim 1, wherein the limitation means is constructed ofat least one of a metal, a plastic, or a composite material.
 7. Theneedle of claim 1, wherein the limitation means is constructed of amaterial selected from the group consisting of PDMS, polyimide,polypropylene, PEEK, polycarbonate, an acetyl film, polyoxymethyleneplastic, gold, stainless steel, nickel, and chrome.
 8. The needle ofclaim 1, wherein the tip is conically-shaped.
 9. The needle of claim 1,wherein the fluid exit port is positioned intermediate to the tip andthe limitation means.
 10. An implantable drug-delivery device,comprising: a drug reservoir; a needle entry port comprising a throatfor receiving a refill needle therethrough; and a vestibule into whichthe throat opens, the vestibule (i) being wider than the throat, (ii)comprising a stop on a wall opposite the throat for halting progress ofa needle into the vestibule through the throat, and (iii) being in fluidcommunication with the drug reservoir.
 11. The implantable drug-deliverydevice of claim 10, wherein the stop is sized so as to halt the progressof a needle comprising an exit port at a point at which the exit port isin fluid communication with the vestibule.
 12. The implantabledrug-delivery device of claim 10, wherein a top surface of the stop iscup-shaped.
 13. The implantable drug-delivery device of claim 10,wherein the stop is constructed of a biocompatible material.
 14. Theimplantable drug-delivery device of claim 10, wherein the stop isconstructed of at least one of a metal, a plastic, or a compositematerial.
 15. The implantable drug-delivery device of claim 10, whereinthe stop is constructed of a material selected from the group consistingof PDMS, polyimide, polypropylene, PEEK, polycarbonate, an acetyl film,polyoxymethylene plastic, gold, stainless steel, nickel, and chrome. 16.The implantable drug-delivery device of claim 10 further comprising acheck valve located between the vestibule and the drug reservoir. 17.The implantable drug-delivery device of claim 10, wherein the needleentry port further comprises a self-sealing material.
 18. An implantabledrug-delivery device, comprising: a drug reservoir; a needle entry portcomprising a throat for receiving a refill needle therethrough, thethroat opening into a vestibule that is in fluid communication with thedrug reservoir; and a visualization ring surrounding the needle entryport, the visualization ring being visible through ocular tissue so asto visually indicate a position of the needle entry port.
 19. Theimplantable drug-delivery device of claim 18, wherein the visualizationring is constructed of a biocompatible material.
 20. The implantabledrug-delivery device of claim 18, wherein the visualization ring isconstructed of a material that withstands penetration by the refillneedle.
 21. The implantable drug-delivery device of claim 18, whereinthe visualization ring is visible through a patient's conjunctiva. 22.The implantable drug-delivery device of claim 18, wherein thevisualization ring comprises a fluorescent pigment.
 23. The implantabledrug-delivery device of claim 22, wherein the fluorescent pigment isselected from the group consisting of a luminescent aerogel, ananoparticle, a phthalocyanine pigment, fluorescein isothiocyanate,rhodamine, coumarin, cyanine, an Alexa Fluor, a DyLight Fluor, a quantumdot, a green fluorescent protein, and a luciferin.
 24. The implantabledrug-delivery device of claim 18, wherein the visualization ringcomprises a light emitting diode.
 25. The implantable drug-deliverydevice of claim 18 further comprising a light emitting diode and opticalfiber for conducting light from the light emitting diode to and aroundthe visualization ring.
 26. The implantable drug-delivery device ofclaim 18, wherein the visualization ring comprises a material thatenhances surface echogenicity and acoustic shadowing.
 27. Theimplantable drug-delivery device of claim 18 further comprisingelectronics to move or vibrate the visualization ring.
 28. Theimplantable drug-delivery device of claim 18, wherein the visualizationring comprises a magnetic material.
 29. A method for refilling adrug-delivery device implanted within a patient, comprising: inserting,into a needle entry port of the drug-delivery device, a distal tip of aneedle that comprises a hollow shaft and a stop on the shaft; advancingthe needle into the needle entry port until the stop limits furtherentry of the needle into the entry port; and delivering drug through thehollow shaft of the needle, out a fluid exit port positioned along theshaft of the needle proximate the tip, and into the drug-deliverydevice.
 30. The method of claim 29, wherein the stop is a ringsurrounding the shaft of the needle, the ring having an outer diameterexceeding a width of the entry port.
 31. The method of claim 29 furthercomprising locating, prior to inserting the distal tip of the needleinto the needle entry port, a visualization ring visually indicating theposition of the needle entry port.
 32. The method of claim 31, whereinthe visualization ring surrounds the needle entry port and is visiblethrough the patient's conjunctiva.
 33. A method for refilling adrug-delivery device implanted within a patient, comprising: inserting,into a needle entry port of the drug-delivery device, a distal tip of aneedle; advancing the needle through the needle entry port into avestibule of the drug-delivery device until a stop positioned on a wallof the vestibule opposite the needle entry port halts further entry ofthe needle; and delivering drug through a hollow shaft of the needle,out a fluid exit port positioned along the shaft of the needle proximatethe tip, and into the vestibule.
 34. The method of claim 33, wherein thestop halts further entry of the needle at a point at which the exit portof the needle is in fluid communication with the vestibule.
 35. Themethod of claim 33 further comprising locating, prior to inserting thedistal tip of the needle into the needle entry port, a visualizationring visually indicating the position of the needle entry port.
 36. Themethod of claim 35, wherein the visualization ring surrounds the needleentry port and is visible through the patient's conjunctiva.